Some N, N′ disubstituted piperazines, specifically those with N-aryl substitution, act on the central nervous system (e.g., bind to 5HT receptors). The J. Med. Chem. (1995), 38(20), 4044–55 and JP 61152655 teach the conventional approach to synthesize the aryl piperazine core, which involves reacting anilines with bis(dichloroethyl)amine. The resulting piperazines are elaborated by alkylating the resulting secondary amine.

A “reversed” version of this chemistry is also possible. In this approach, an aniline mustard-like intermediate reacts with an alkyl amine, as shown, for example, in J. Labeled Compounds and RadioPharm. (1986) Vol XXIV, No. 4,351. However, the commercial availability of bis(2-cholorethyl)amine hydrochloride relative to the general availability of aniline mustards makes this approach less attractive.

Asymmetric aryl piperazines are also formed by coupling piperazines with aryl triflates or bromides. Tetrahedron Letters (1998), 39, 2219 indicates that yields for this process are very (aryl) substrate dependent and generally are low.

The formation of piperazines bearing a chiral center directly on nitrogen is the present invention's focus. Some methods for the formation of chiral N-piperazines are known. One known method is to resolve a racemic mixture, which has the disadvantage of wasting half the material.
Another known method is to displace a leaving group attached to a chiral center with an aryl piperazine. The barrier to displacement of the hindered leaving group is a problem, however. Enhancing the leaving group's reactivity creates other problems: JP 01125357 teaches that benzyl-(S)-bromopropionate reacts with 1-benzylpiperazine to give the expected (R) isomer displacement product. The carbonyl group, while activating the displacement process, also increases the susceptibility of the adjacent chiral center toward racemization under the reaction conditions.
WO 95/33743 reports an alternative that eliminates the racemization problem of activation by utilizing a chiral cyclic sulfamate as the reactive alkylating agent.
While cyclic sulfamates react readily with piperazines, the sulfamate itself requires numerous steps to prepare. In the case where R=2-pyridyl, for example, four separate chemical steps or transformations are required.
In Acta Pol. Pharm., 56 (1), 41–47; 1999 it is reported that chiral amino acids reacting with N-methyl-N,N-bis(2-chloroethane). The carboxylic acid function makes the chiral center susceptible to racemization both during the reaction and during subsequent synthetic manipulations.
In another approach, J. Med Chem. 30(10), 1779–87; 1987 reports chiral benzyl amines react with a variety of mustards, both N-alkyl and N-aryl. The chiral amines employed were obtained by resolution.
WO94/24115 teaches the reaction of β-alkyl(and aryl)oxy chiral amines with mustards to form piperazine compounds.
To date, most syntheses of N-aryl N′ substituted piperazines involve pre-forming the N-aryl piperazine followed by alkylation on N′. This approach is an efficient way to prepare many compound types. However, it is of limited practicality for the introduction of chirality α to the nitrogen because it relies on chiral alkylating agents that require multi-step syntheses to prepare.